Sepsis Septic shock

1. SepsisSeptic shock Reuben Ramphal M.D. Division of Infectious Diseases University of Florida

2. Occurrence of Severe Sepsis Annual incidence: ~750,000 cases in US 2.26 cases per 100 hospital discharges 51.1% received ICU care and 17.3% received IMC care Incidence and mortality increased with age Case fatality rate: 28% Economic burden $22,100 per case ~$16.7 billion nationally

3. Reference Diseases Incidence in US (cases per 100,000) AIDS1 17 Colon and rectal cancer2 48 Breast cancer2 112 Congestive heart failure3 ~196 Severe sepsis4 ~300 Number of deaths in US each year Acute myocardial infarction5 218,000 Severe sepsis4 215,000

4. Sepsis on the Rise Incidence projected to rise during the next decade Aging population especially in developed nations Increased awareness and diagnosis Immunocompromised patients e.g. cancer therapy, transplantation) Invasive procedures (ventilators, catheters, prostheses) Resistant pathogens

5. Definitions

6. Systemic Inflammatory Response Syndrome Systemic Inflammatory Response Syndrome (SIRS)--the beginning of illness ? 2 of the following: Temp > 38?C or < 36?C Heart rate > 90 bpm Respiratory rate > 20 bpm WBC > 12,000, < 4,000 or bands > 10%

7. Sepsis Sepsis SIRS + infection Severe sepsis Sepsis with organ dysfunction, hypoperfusion or hypotension Septic Shock Sepsis with hypotension and perfusion abnormalities despite adequate volume replacement

10. Why do people die from Sepsis? Very few organisms produce toxins that cause death directly Diptheria Tetanus, botulism Pseudomonas aeruginosa ? Death from sepsis is mainly due to inflammation

11. Pathogenesis of Sepsis A wide variety of microorganisms cause sepsis How--there must be some common mechanism Interaction of specific Pathogen Associated Molecular Patterns (PAMPs)with Toll-like receptors (Tlrs) PAMPs - highly conserved parts of microbial molecules on organisms-Lps, peptidoglycan,flagellin Tlrs -ancient receptors conserved on animal and plant cells Sepsis may also caused by interactions of super antigens with receptors on T- cells e.g. some staphylococcal and streptococcal toxins

12. Innate Immune response Sepsis Interaction of a microbial signature with a toll-like receptor leads to activation of innate immune mechanisms Message sent to nucleus resulting in transcription of repressed genes Antimicrobial peptide (DEFENSINS) synthesis and release which can kill most organisms Release of Mediators of inflammation - cytokines, chemokines PMN leucocytes come into the site of inflammation to phagocytize organisms--release enzymes Normally protective but either overwhelmed by bacterial inocula or some type of dysregulation leads to severe SEPSIS

15. Pathogenesis of Severe Sepsis

17. Most Effective therapies Early recognition of preshock- tachynea leading to respiratory alkalosis Low Pco2, pH >7.45 Lots of intravenous Fluids Antibiotics Effective antibiotics Timely administration of Effective antibiotics

25. Choosing the RIGHT antibiotic in Sepsis Site of Infection, if known it helps to limit choices intraabdominal, or necrotizing soft tissue infection needs anaerobic coverage. Skin infections require gram positive coverage Lung most common site of documented infection-P. aeruginosa, S. aureus, Know resistance picture in hospital ESBLs, P. aeruginosa, choose best drugs against these Know resistance in community if sepsis is community acquired - S. aureus, S. pneumoniae, E.coli Give the antibiotic as soon as possible

26. Primary Sites of Infection in a recent large study of Septic shock

27. Antibiotic Choices Given the world wide resistance issues the most effective antibiotic choices to cover gram negatives would be Fourth generation cephalosporins � aminoglycoside (Geographic location) Carbapenems � aminoglycoside (Pseudomonas resistance during therapy of Lung infections) Pip-Tazobactam + an aminoglycoside (Esbl resistance) If the incidence of MRSA is high and gram positive coverage is needed, add an anti Staphylococcal agent --Vanco, Teicoplanin

34. Reversal of shock in response to steroids Kaplan�Meier Curves for the Time to Reversal of Shock. For the comparison between patients with septic shock who received hydrocortisone and those who received placebo, P = 0.06 for patients who did not have a response to a corticotropin test (Panel A) and P<0.001 for patients who had a response to corticotropin (Panel B)

35. Survival at 28 days in response to steroids Kaplan�Meier Curves for Survival at 28 Days. For the comparison between patients with septic shock who received hydrocortisone and those who received placebo, there was no significant difference among those who did not have a response to a corticotropin test (Panel A),those who had a response to corticotropin (Panel B).

36. Optimum therapy of Sepsis and Shock Antibiotics remain the most critical choice to be made TIMELY-reduces mortality EFFECTIVE, BROAD SPECTRUM-reduces mortality DIFFERENT antibiotics for different patients P. aeruginosa continues to be associated with highest mortality Resistance issues need to be kept in mind A large number of patients with the sepsis syndrome will not have an organism cultured but should be treated with antibiotics Prevent the development of septic shock - fluids and Right antibiotics